The targeted disease is retinitis pigmentosa (RP), is a severe form of blindness that runs in families. This disease is not overly common, yet represents an attainable near term target for stem cell therapy for a number of reasons: 1) RP destroys the light detecting cells of the retina but generally leaves the rest of the visual system and body unharmed, so the clinical goal is circumscribed; 2) RP is prototypical of degenerations of the nervous system, so a cure for this less common disease would accelerate progress towards new therapies for a range of more familiar conditions; 3) scientific research has shown that degenerating rods and cones can be spared in animals by transplanting particular types of stem cells, so the scientific feasibility of treating RP in this way has already been established in principle.
The therapeutic approach is to save the light sensing cells of the eye (rod and cone photoreceptors) in people going blind using a type of stem cell obtained from the immature retina, but not from early embryos. These particular stem cells from the retina, known as progenitor cells, are capable of rescuing photoreceptors from degeneration following transplantation to the eye. These same cells are also highly efficient at becoming rod photoreceptors and this provides another more sustained pathway by which they preserve the crucial cone photoreceptors. In addition, there is evidence that the stem cells themselves might become functional photoreceptors and thereby stabilize the retina by directly replacing the dying cells in the patient’s eye. Thus, transplanted stem cells could treat the targeted disease of RP in multiple ways simultaneously. Importantly, there are a host of reasons why clinical trials in the eye are easier and safer than most locations in the body. The eye is an important proving ground for stem cell-based therapies and provides a stepping stone to many otherwise incurable diseases of the brain and spinal cord.

Statement of Benefit to California:

Benefits to the state of California and its citizens are both direct and indirect. The direct benefit is medical in that there is currently no cure or established treatment for the individuals and families that suffer from the dreadful hereditary blindness known as retinitis pigmentosa. In addition, there are many people in California and throughout the world that suffer from degenerative diseases of the retina and central nervous system that could benefit from further development and alternate applications of the type of stem cell therapy proposed in the current application. The rapid progress that could be achieved via this proposal would help legitimize the use of stem cells and should thereby accelerate the development of stem cell-based therapeutics for a wide range of other diseases. In so doing there would be an indirect benefit to California by making our state a focal point for stem cell breakthroughs. This would increase medical capabilities, strengthen the [REDACTED], and energize local biotechnology companies with outside investment and a payoff in jobs and tax revenues.

Review Summary:

This Development Candidate proposal describes a plan to utilize allogeneic retinal progenitor cells (RPC) as a therapy for Retinitis Pigmentosa (RP). RP is a well-characterized, progressive genetic disease in which photoreceptors degenerate. The initial loss of rods is a prelude to the subsequent loss of cones, which culminates in total blindness. The applicants will first develop standardized methods for RPC generation, characterization and in vivo testing. Next, they will apply these methods to both generate a cell bank and perform initial preclinical efficacy and safety studies.
Reviewers praised this proposal’s compelling objective and scientific rationale. They found RPC an ideal cell choice for RP treatment. RPC have the potential to integrate into the retina, give rise to new rod photoreceptors and protect cone photoreceptors in degenerative conditions. Further, the applicant and others have published that RPC can improve visual function in animal models. The cells appear to be immune privileged, and therefore well suited for allogeneic applications. Recent clinical work has also supported benefit from cell-derived trophic support in retinal disease. Reviewers agreed RP represents a wise choice for a first indication for a regenerative retinal therapy as RP is an orphan disease with no current treatment. In addition, RP patients are young, otherwise healthy and will develop complete blindness absent an effective therapy. Therefore, if successfully developed, this novel stem cell-based cell therapy could have great impact on the disease. Ultimately, this work could be applied to other retinal pathologies.
Reviewers found the research plan focused, well thought out and complete. They stated that accomplishment of the specific aims would result in an RPC development candidate ready for IND enabling development. Further, reviewers noted the impressive body of preliminary results supporting project feasibility. The panel appreciated the careful consideration of the many complex activities required to develop a safe, effective cell therapy including: optimizing culture conditions, achieving adequate cell purity, assessing genetic stability, developing potency assays and demonstrating reproducible disease modifying activity. The early development of the research cell bank that was GMP compatible was another strength of the program. Reviewers appreciated the proposal’s alternative plans, found the milestones clear and timeline to achieve the proposed work realistic. However, reviewers express some minor concerns. They cautioned the selected RPC source could prove limiting and that some proposed activities, specifically pivotal biodistribution and tumorigenicity studies are IND-enabling toxicology studies which would be out of scope of the RFA. Despite these caveats, the panel remained unanimously supportive of the proposal.
Reviewers agreed that the PI is eminently qualified to lead the proposed translational program. The PI has relevant training and publications in retinal regeneration and has proactively planned for program operations, support and team communications. The team is highly qualified, well trained and has an established record of working together. Further, collaborations the PI has formed with experts in retinal analysis and surgery add considerably to the program’s potential for success. Levels of commitment are appropriate to accomplish the proposal’s aims. The budget is appropriate . Reviewers also appreciated the issued intellectual property, excellent research environment and strong support for translation research at the host institution.
In summary, this application describes a plan to achieve a development candidate for RP using allogeneic human RPC. Reviewers were highly enthusiastic and uniformly recommended this application for funding because its superb PI, sound rationale, compelling preliminary data, and complete, well-reasoned research plan gave it an excellent chance of success.